Mutations in the dystrophin-associated proteins, gamma- and delta- sarcoglycan, have been shown to cause both cardiomyopathy and muscular dystrophy in humans. It has recently been shown that dominant negative mutations in delta-sarcoglycan can cause dilated cardiomyopathy in humans. This is in contrast to the null mutations that have previously been shown to produce muscle and heart degeneration in humans and mice. Delta-sarcoglycan is a 35 kD type II transmembrane protein. Delta sarcoglycan is expressed in heart, skeletal and smooth muscle and forms an integral part of the sarcoglycan complex. We plan to study these dominant negative mutations in cell culture as well as transgenic mice in order to ascertain their effects on other components of the dystrophin glycoprotein complex including dystrophin, laminin, filamin and nitric oxide synthase. We are proposing to study heterozygous mutations in delta-sarcoglycan because these mutations likely result in disrupted interactions within the j dystrophin-glycoprotein complex. Therefore, we will gain an increased understanding of the etiology of dilated cardiomyopathy through the investigation of delta-sarcoglycan.